Composition for controlled ovarian stimulation

ABSTRACT

Preparations including FSH, for example recombinant FSH, for use in the treatment of infertility in patients having high AMH and low bodyweight.

The present invention relates to compositions and pharmaceuticalproducts for the treatment of infertility.

Assisted reproductive technology (ART) techniques such as in vitrofertilisation (IVF) are well known. These ART techniques generallyrequire a step of controlled ovarian stimulation (COS), in which acohort of follicles is stimulated to full maturity. Standard COSregimens include administration of gonadotrophins, such as folliclestimulating hormone (FSH), alone or in combination with luteinisinghormone (LH) activity to stimulate follicular development, normally withadministration of a GnRH analogue prior to and/or during stimulation toprevent premature LH surge. The pharmaceutical compositions generallyused for COS include recombinant follicle stimulating hormone (rFSH)including Rekovelle® and Gonal F, urinary derived FSH, recombinantFSH+LH preparations, urinary derived menotrophin [human menopausalgonadotrophin (hMG)] and highly purified human menopausal gonadotrophin(HP-hMG). IVF can be associated with a risk of ovarian hyperstimulationsyndrome (OHSS), which can be life threatening in severe cases.

The ability to predict the response potential of women to controlledovarian stimulation (COS) may allow the development of individualisedCOS protocols. Such individualised protocols could, for example, reducethe risk of OHSS in women predicted to have an excessive response tostimulation, and/or improve pregnancy outcomes in women classed as poorresponders. The serum concentration of anti-Mllerian hormone (AMH) isnow established as a reliable marker of ovarian reserve. Decreasinglevels of AMH are correlated with reduced ovarian response togonadotrophins during COS. Further, high levels of AMH are a goodpredictor of excessive ovarian response, and an indicator of risk ofOHSS.

In a preliminary study of women under 35 years old undergoing ART, theCONSORT dosing algorithm (incorporating basal FSH, BMI, age and AFC) wasused to predict the optimal FSH starting dose for COS in women at riskof developing OHSS (Olivennes et. al., 2009). Individualising the doseled to adequate oocyte yield and good pregnancy rate. However, therewere high rates of cancellations in the low dose group (75 IU FSH) dueto inadequate response, and OHSS did occur in a significant proportionof the patients.

There is therefore a need for individualised COS protocols which provideadequate response to stimulation, and/or decreased risk of OHSS.

As indicated above, standard COS protocols may include administration ofFSH. FSH is naturally secreted by the anterior pituitary gland andfunctions to support follicular development and ovulation. FSH comprisesa 92 amino acid alpha sub-unit, also common to the other glycoproteinhormones LH and CG, and a 111 amino acid beta sub-unit unique to FSHthat confers the biological specificity of the hormone (Pierce andParsons, 1981). Each sub-unit is post translationally modified by theaddition of complex carbohydrate residues. Both subunits carry 2 sitesfor N-linked glycan attachment, the alpha sub-unit at amino acids 52 and78 and the beta sub-unit at amino acid residues 7 and 24 (Rathnam andSaxena, 1975, Saxena and Rathnam, 1976). FSH is thus glycosylated toabout 30% by mass (Dias and Van Roey. 2001. Fox et al. 2001).

FSH purified from post-menopausal human urine has been used for manyyears in infertility treatment; both to promote ovulation in naturalreproduction and to provide oocytes for assisted reproductiontechnologies. Until recently, the only approved recombinant FSH (rFSH)products for ovarian stimulation, such as follitropin alfa (GONAL-F,Merck Serono/EMD Serono) and follitropin beta (PUREGON/FOLLISTIM,MSD/Schering-Plough), were derived from a Chinese Hamster Ovary (CHO)cell line.

There is considerable heterogeneity associated with FSH preparationswhich relates to differences in the amounts of various isoforms present.Individual FSH isoforms exhibit identical amino acid sequences butdiffer in the extent to which they are post-translationally modified;particular isoforms are characterised by heterogeneity of thecarbohydrate branch structures and differing amounts of sialic acid (aterminal sugar) incorporation, both of which appear to influence thespecific isoform bioactivity.

Glycosylation of natural FSH is highly complex. The glycans in naturallyderived pituitary FSH can contain a wide range of structures that caninclude combinations of mono-, bi-, tri- and tetra-antennary glycans(Pierce and Parsons, 1981. Ryan et al., 1987. Baenziger and Green,1988). The glycans can carry further modifications: core fucosylation,bisecting glucosamine, chains extended with acetyl lactosamine, partialor complete sialylation, sialylation with α2,3 and α2,6 linkages, andsulphated galactosamine substituted for galactose (Dalpathado et al.,2006). Furthermore, there are differences between the distributions ofglycan structures at the individual glycosylation sites. A comparablelevel of glycan complexity has been found in FSH derived from the serumof individuals and from the urine of post-menopausal women (Wide et al.,2007).

The glycosylation of recombinant FSH products reflects the range ofglycosyl-transferases present in the host cell line. Commerciallyavailable rFSH products derived from engineered Chinese hamster ovarycells (CHO cells) have a more limited range of glycan modifications thanthose found on the natural products. Examples of the reduced glycanheterogeneity found in CHO cell derived rFSH include a lack of bisectingglucosamine and a reduced content of core fucosylation and acetyllactosamine extensions (Hard et al., 1990). In addition, CHO cells areonly able to add sialic acid using the α2,3 linkage (Kagawa et al, 1988,Takeuchi et al, 1988, Svensson et al., 1990); CHO cell derived rFSH onlyincludes α2,3-linked sialic acid and does not include α2,6-linked sialicacid.

Thus CHO cell derived FSH is different from naturally produced FSH (e.g.human pituitary/serum/urinary FSH) which contains glycans with a mixtureof α2,3 and α2,6-linked sialic acid, with a predominance of the former.

The present applicants have developed a human cell line derivedrecombinant FSH which is the subject of International Patent ApplicationNo. PCT/GB2009/000978, published as WO2009/127826A. Recombinant FSH witha mixture of both α2,3 and α2,6-linked sialic acid was made byengineering a human cell line to express both rFSH and α2,3sialyltransferase. The expressed product is highly acidic and carries amix of both α2,3- and α2,6-linked sialic acids; the latter provided bythe endogenous sialyl transferase activity. It was found that the typeof sialic acid linkage, α2,3- or α2,6-, can have a dramatic influence onbiological clearance of FSH. Recombinant FSH with a mixture of both α2,3and α2,6-linked sialic acid has two advantages over rFSH expressed inconventional CHO cells: first the material is more highly sialylated dueto the combined activities of the two sialyltransferases; and secondlythe material more closely resembles the natural FSH. This is likely tobe more biologically appropriate compared to CHO cell derivedrecombinant products that have produce only α2,3 linked sialic acid(Kagawa et al, 1988, Takeuchi et al, 1988, Svensson et al., 1990) andhave decreased sialic acid content (Ulloa-Aguirre et al. 1995., Andersenet al. 2004).

The amino acid sequence of the human cell line derived recombinant FSHwhich is the subject of International Patent Application No.PCT/GB2009/000978, published as WO2009/127826A, is the native sequenceand is identical to natural human FSH and existing CHO-derived rFSHproducts. However, the present applicants have found that human derivedrecombinant FSH products (i.e. recombinant FSH produced or expressed ina human cell line e.g. made by engineering a human cell line) which havea mixture of both α2,3 and α2,6-linked sialic acid may be particularlyeffective when utilised in (e.g. individualised) COS protocols.

On 13 Dec. 2016, the European Commission (EC) granted marketingauthorisation for REKOVELLE® (follitropin delta, also known asFE999049), a human cell line derived recombinant follicle stimulatinghormone (human rFSH), for use in controlled ovarian stimulation for thedevelopment of multiple follicles in women undergoing assistedreproductive technologies (ART), such as an in vitro fertilisation (IVF)or intracytoplasmic sperm injection (ICSI) cycle. REKOVELLE® is thefirst rFSH to be derived from a human cell line. The REKOVELLE®(follitropin delta) product is produced by the methods disclosed inInternational Patent Application No. PCT/GB2009/000978.

Two randomised, controlled, assessor-blind, parallel groups,multi-centre phase 2 anti-Müllerian hormone (AMH)-stratified trials wereconducted in IVF/ICSI patients, one in Europe and one in Japan, with thepurpose of determining the dose-response relationship of FE 999049 andthe number of oocytes retrieved. In both trials, randomisation wasstratified according to AMH levels at screening; low AMH (5.0-14.9pmol/L) or high AMH (15.0-44.9 pmol/L). In the European dose-responsephase 2 trial, five doses of FE 999049 ranging from 5.2 pg/day to 12.1pg/day were investigated and a reference group of an approved rFSHproduct (GONAL-F, 150 IU/day) was also included. In the Japanesedose-response phase 2 trial, three doses of FE 999049 (6 μg/day, 9μg/day and 12 μg/day) were investigated and a standard therapy of theapproved rFSH product (FOLLISTIM, 150 IU/day) was also included. Atpresent, follitropin beta (FOLLISTIM) is the only medicinal productapproved in Japan for controlled ovarian stimulation in IVF/ICSI cycles.

In the European and the Japanese phase 2 trials, the daily dose wasfixed throughout the stimulation period. In both trials, a statisticallysignificant dose response relationship for FE 999049 with respect to thenumber of oocytes retrieved was observed for the overall population andfor each AMH randomisation stratum. Acceptable pregnancy rates wereachieved with all FE 999049 doses. Furthermore, the observed FE 999049dose-response profile was similar in the European trial and in theJapanese trial.

This work enabled the development of individualised COS protocols fordosing the REKOVELLE® (follitropin delta, FE999049) product.

The applicants have found that it is generally necessary to retrieve inthe region of nine oocytes in order to enable selection of two highquality oocytes for transfer.

The applicants have found that for subjects having low AMH (AMH<15pmol/L per litre) a reasonably high dose of follitropin delta isrequired (for example 12 μg) to achieve this. At this dose, 8 to 14oocytes will be retrieved from 60% of subjects with low AMH. This is anunexpected and significant improvement over treatment of subjects withlow AMH treated with 150 IU Gonal-f, where 8 to 14 oocytes are retrievedfrom only 33% of subjects. The applicants have found that there is noneed to adjust this dose according to the bodyweight of the patient.

However, 60% of the population (and 80% of women under 30 treated forinfertility) have high AMH (that is, AMH of ≥15 pmol/L). For thesesubjects it is generally fairly straightforward to retrieve a mean of 9to 11 oocytes; the problem with stimulation protocols is the risk ofOHSS. The applicants have found that in patients dosed at low doses offollitropin delta there is a relationship between oocytes retrieved andbody weight of the subject. This means that there may be a riskassociated with treatment with a fixed dose of FSH (which is usual inthe art). The present applicants have established a relationship betweendose of FSH and AMH level and weight of the subject which provides animproved safety profile (reduced risk of OHSS) with acceptable orimproved oocyte retrieval compared to the known treatment protocols.

The posology of REKOVELLE is individualised for each patient and aims toobtain an ovarian response which is associated with a favourablesafety/efficacy profile, i.e. aims to achieve an adequate number ofoocytes retrieved and reduce the interventions to prevent ovarianhyperstimulation syndrome (OHSS). REKOVELLE is dosed in micrograms.

For the first treatment cycle, the individual daily dose will bedetermined on the basis of the woman's serum anti-Müllerian hormone(AMH) concentration and her body weight. The dose should be based on arecent determination of AMH (i.e. within the last 12 months) measured bythe following diagnostic test from Roche: ELECSYS AMH Plus immunoassay.The individual daily dose is to be maintained throughout the stimulationperiod.

For women with AMH<15 pmol/L the daily dose of REKOVELLE is 12micrograms, irrespective of body weight.

For women with AMH≥15 pmol/L the daily dose of REKOVELLE decreases from0.19 to 0.10 micrograms/kg by increasing AMH concentration (Table 1,below).

The dose is to be rounded off to the nearest 0.33 micrograms to matchthe dosing scale on the injection pen. The maximum daily dose for thefirst treatment cycle is 12 micrograms. For calculation of the REKOVELLEdose, the body weight is to be measured without shoes and overcoat justprior to start of stimulation.

TABLE A Dosing regimen AMH <15 15-16 17 18 19-20 21-22 23-24 25-27 28-3233-39 ≥40 (pmol/L) Fixed daily 12.0 0.19 0.18 0.17 0.16 0.15 0.14 0.130.12 0.11 0.10 dose of mcg mcg/kg mcg/kg mcg/kg mcg/kg mcg/kg mcg/kgmcg/kg mcg/kg mcg/kg mcg/kg REKOVELLE mcg: micrograms

The AMH concentration is to be expressed in pmol/L and is to be roundedoff to the nearest integer. If the AMH concentration is in ng/mL, theconcentration should be converted to pmol/L by multiplying with 7.14(ng/mL×7.14=pmol/L) before use.

Treatment with REKOVELLE should be initiated day 2 or 3 after start ofmenstrual bleeding, and continue until adequate follicular development(≥3 follicles ≥17 mm) has been achieved, which on average is by theninth day of treatment (range 5 to 20 days). A single injection of 250micrograms recombinant human chorionic gonadotropin (hCG) or 5,000 IUhCG is administered to induce final follicular maturation. In patientswith excessive follicular development (of ≥25 follicles ≥12 mm),treatment with REKOVELLE should be stopped and triggering of finalfollicular maturation with hCG should not be performed.

For subsequent treatment cycles, the daily dose of REKOVELLE should bemaintained or modified according to the patient's ovarian response inthe previous cycle. If the patient had adequate ovarian response in theprevious cycle without developing OHSS, the same daily dose should beused. In case of ovarian hypo-response in the previous cycle, the dailydose in the subsequent cycle should be increased by 25% or 50%,according to the extent of response observed. In case of ovarianhyperresponse in the previous cycle, the daily dose in the subsequentcycle should be decreased by 20% or 33%, according to the extent ofresponse observed. In patients who developed OHSS or were at risk ofOHSS in a previous cycle, the daily dose for the subsequent cycle is 33%lower than the dose the cycle where OHSS or risk of OHSS occurred. Themaximum daily dose is 24 micrograms.

The efficacy and safety of the FE 999049 individualised dosing regimenbased on the woman's serum AMH and body weight has been confirmed in alarge phase 3 trial, ESTHER-1 (Evidence based Stimulation Trial withHuman rFSH in Europe and Rest of World), conducted in 11 countriesincluding Europe, North America and Latin America. The ESTHER-1 trialwas conducted in 1,326 IVF/ICSI patients who were randomised 1:1 tocontrolled ovarian stimulation with one of the following treatments: 1)FE 999049 in its individualised dosing regimen with the daily dose fixedthroughout simulation, or 2) an approved CHO-derived rFSH product(follitropin alfa, GONAL-F) at a standard starting dose of 150 IU/dayfollowed by dose adjustments based on the subject's follicular responseduring stimulation. FE 999049 in its individualised dosing regimen wasdemonstrated to be non-inferior to follitropin alfa with respect toongoing pregnancy rate (30.7% versus 31.6%) and ongoing implantationrate (35.2% versus 35.8%). For the overall population, there was nostatistically significant difference between treatment groups in termsof number of oocytes retrieved, with an average of 10.0 for FE 999049and 10.4 for follitropin alfa. Nevertheless, the individualised FE999049 dosing regimen in comparison to follitropin alfa led tostatistically significantly more oocytes retrieved among patients withAMH<15 pmol/L (population at risk of hyporesponse) with an average of8.0 versus 7.0 and statistically significantly fewer oocytes amongpatients with AMH≥15 pmol/L (population at risk of hyperresponse) withan average of 11.6 versus 13.3. The immediate clinical relevance of thisshift in ovarian response with FE 999049 therapy was realised asstatistically significantly fewer patients with extreme ovarian responsecompared to follitropin alfa, i.e. <4 oocytes among patients with AMH<15pmol/L (12% versus 18%) and ≥15 or ≥20 oocytes among patients withAMH≥15 pmol/L (28% versus 35%, and 10% versus 16%). The percentage ofpatients with an appropriate ovarian response, defined for FE 999049 as8-14 oocytes, was reached by statistically significantly more patientstreated with FE 999049 compared to follitropin alfa, i.e. 43% versus38%, despite implementation of dose adjustments during stimulation for37% of the patients in the follitropin alfa group in contrast to thefixed-dose individualised dosing regimen for FE 999049. A statisticallysignificantly lower total gonadotropin dose in the FE 999049 groupcompared to the CHO-derived rFSH product group was observed with anaverage of 90 μg and 104 μg, respectively.

The most serious risk associated with gonadotropin treatment is ovarianhyperstimulation syndrome (OHSS). Overall, in the ESTHER-1 phase 3trials, OHSS and/or preventive interventions of early OHSS occurred in4.4% of the FE 999049 cycles and 6.5% of the follitropin alfa cycles.Moderate/severe OHSS and/or preventive interventions for early OHSS wereobserved at an incidence of 3.3% and 5.6% of the treatment cycles withFE 999049 and follitropin alfa, respectively.

Previous studies have reported OHSS rates in Japanese patients between5% and 28.3%. In the FE 999049 phase 2 trial in Japan, the incidence ofearly moderate/severe OHSS was 19.5% for subjects in the FOLLISTIMgroup. Despite the variation in the OHSS incidence reporting, the highOHSS incidence in Japanese IVF/ICSI patients illustrates a clear need inJapan for a treatment option with a safer OHSS profile. Based on morethan 1,300 cycles in the ESTHER-1 phase 3 trial, the individualiseddosing regimen of FE 999049 was associated with a statisticallysignificant reduction in the proportion of subjects with early OHSSand/or preventive interventions for early OHSS in comparison to thestandard regimen of CHO-derived rFSH product, with an incidence of 4.7%in the FE 999049 group and 6.2% in the follitropin alfa group.

In many Asian populations (for example Japan, China, South Korea andIndia), many women have a low body weight, compared to women in the USand Western Europe. There is therefore a risk that administering a fixeddose, suitable for the general population in Europe, to Asian/Japanesepatients, could lead to these lighter patients receiving a dose of FSHwhich is overly high in terms of dose/kg body weight. This in turn couldlead to risk of over-response and OHSS in these patients. Thetraditional “fixed dose” FSH protocols may be a factor in some highreported OHSS rates in Japan.

The dose protocol set out in Table A goes some way to mitigating thisrisk because patients are dosed by bodyweight. However, very low dosesof gonadotropins are potentially associated with inadequate follicularrecruitment and poor ovarian response. There is therefore a risk thatdosing according to the Table A protocol might lead to very lightpatients with high AMH receiving a dose of FSH which may be sub-optimalfrom an efficacy perspective. There is therefore a need for effectivedosing of lighter patients (weight <60 kg) with high AMH while reducingrisk of overstimulation and OHSS in these patients (who may be moreprone to this risk because they have high AMH and low bodyweight).

The present applicants identified patients in the Japanese phase 2 trialmentioned above (see also Example 2 below) who (based on AMH and bodyweight) would have received <6 μg FE 999049 according to theindividualised FE 999049 dosing regimen set out in Table A, but actuallyreceived either 6 μg FE 999049 or 150 IU FOLLISTIM as per randomisation.This was only a very limited number of patients (5 patients in the 6 μgFE 999049 group, and 3 patients in the 150 IU FOLLISTIM group).Surprisingly, ovarian response of 15 oocytes or more was not observed inany of the 5 patients in the 6 μg FE 999049 group but in 2 of 3 patients(66.7%) in the 150 IU FOLLISTIM group. Also surprisingly, excessivefollicular development requiring triggering with GnRH agonist was notobserved in any of the 5 patients in the 6 μg FE 999049 group but in 1of 3 patients (33.3%) in the 150 IU FOLLISTIM group. Early OHSS wasreported for 1 of 5 patients (20.0%) in the 6 μg FE 999049 group and for1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group. These datasupport the safe and efficacious use of 6 μg FE 999049 in JapaneseIVF/ICSI patients, including those patients with body weight <60 kg andAMH pmol/L.

The applicants surprisingly found that it is possible to specify aminimum dose of 6 μg to account for the lower body weight in theJapanese population, with the intention of avoiding underdosing ofJapanese patients with low body weight, and thereby maintain efficacy inthese patients, while avoiding side effects such as OHSS. It will beappreciated that this technical effect applies to any Asian population,or indeed any population which includes patients with low bodyweight andhigh AMH irrespective of the patient's ethnic background.

According to the present invention in a first aspect there is provided acomposition (e.g. a pharmaceutical composition) for use in the treatmentof infertility in a patient (e.g. a female patient) having AMH≥15 pmol/L(for example AMH≥16 pmol/L, for example AMH≥19 pmol/L, for exampleAMH≥26 pmol/L, for example AMH≥28 pmol/L, for example AMH≥40 pmol/L) andbodyweight <60 kg, the composition comprising a daily dose of, or adaily dose equivalent to, 6 to 8 μg recombinant FSH. Preferably, thecomposition comprises a daily dose of 6 to 8 μg recombinant FSH. Morepreferably, the composition comprises a daily dose of 6 μg recombinantFSH.

The treatment of infertility may include a step (or steps) ofdetermining the serum AMH level and bodyweight of the patient. Thetreatment of infertility may include a step of administering the dose tothe patient having the defined serum AMH level and bodyweight. Forexample, the treatment of infertility may include a step (or steps) ofdetermining the serum AMH level and bodyweight of the patient, and astep of administering the dose to the patient having AMH 15 pmol/L (forexample AMH≥16 pmol/L, for example AMH≥19 pmol/L, for example AMH≥26pmol/L, for example AMH≥28 pmol/L, for example AMH≥40 pmol/L) andbodyweight <60 kg [e.g. bodyweight <55 kg, for example <52 kg, forexample <50 kg, for example <45 kg].

The step of determining the serum AMH level of the patient may takeplace up to twelve months before the dose is first administered to thepatient. Preferably the serum AMH level of the patient is determined(measured) by the ELECSYS AMH Plus immunoassay (available from Roche, ofSwitzerland, see www.roche.com). The step of determining the bodyweightof the patient may take place just before (e.g. 0 to 2 days before) thedose is first administered to the patient. The step of determining thebodyweight of the patient may use weighing scales, as are well known.

The composition (e.g. pharmaceutical composition) may be for use fortreatment of infertility in a patient having bodyweight <59 kg, forexample <56 kg, for example <55 kg, for example <52 kg, for example <50kg, for example <45 kg, for example <42 kg, for example <31.5 kg. Thecomposition (e.g. pharmaceutical composition) may be for use fortreatment of infertility in a patient having bodyweight from 40 to 59.9kg, for example for treatment of infertility in a patient havingbodyweight from 45 to 55 kg. The composition may be for use fortreatment of infertility in a patient having AMH≥16 pmol/L, for exampleAMH≥19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28 pmol/L, forexample AMH≥30 pmol/L, for example AMH≥40 pmol/L.

Preferably, the composition (e.g. pharmaceutical composition) is for usefor treatment of infertility in a patient having bodyweight <52 kg (forexample 50 kg, for example <45 kg) and having AMH≥26 pmol/L (for exampleAMH≥28 pmol/L, for example AMH≥30 pmol/L, for example AMH≥40 pmol/L). Inthis example the treatment of infertility may include a step ofdetermining the serum AMH level and bodyweight of the patient, and astep of administering the dose to a patient having AMH≥26 pmol/L andbodyweight <52 kg.

According to the present invention in a further aspect there is provideda composition (e.g. a pharmaceutical composition) for use in thetreatment of infertility in a patient (e.g. a female patient) identified(prior to treatment) as having AMH≥15 pmol/L (for example AMH≥16 pmol/L,for example AMH≥19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28pmol/L, for example AMH≥40 pmol/L) and identified (prior to treatment)as having bodyweight <60 kg, the composition comprising a daily dose of,or a daily dose equivalent to, 6 to 8 μg recombinant FSH. Preferably,the composition comprises a daily dose of 6 to 8 μg recombinant FSH.More preferably, the composition comprises a daily dose of 6 μgrecombinant FSH.

The treatment of infertility may include a step of identifying thepatient (prior to treatment) based on the serum AMH level and bodyweightof the patient. The treatment of infertility may include a step ofadministering the dose to the patient identified as having the definedserum AMH level and bodyweight. For example, the treatment ofinfertility may include a step of identifying the patient (prior totreatment) based on the serum AMH level and bodyweight of the patient,and a step of administering the dose to the patient identified (prior totreatment) as having AMH≥15 pmol/L (for example AMH≥16 pmol/L, forexample AMH≥19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28pmol/L, for example AMH≥40 pmol/L) and identified (prior to treatment)as having bodyweight <60 kg [e.g. bodyweight <55 kg, for example <52 kg,for example <50 kg, for example <45 kg].

The step of identifying the patient (prior to treatment) based on theserum AMH level and bodyweight of the patient may take place just before(e.g. 0 to 2 days before) the dose is first administered to the patient.The step of identifying the patient may be based on a serum AMH leveldetermined previously (e.g. a serum AMH level determined up to twelvemonths before the dose is first administered to the patient). Preferablythe serum AMH level of the patient is determined (measured) by theELECSYS AMH Plus immunoassay (available from Roche, of Switzerland, seewww.roche.com). The step of identifying the patient may be based on abodyweight of the patient determined just before (e.g. 0 to 2 daysbefore) the dose is first administered to the patient. The step ofdetermining the bodyweight of the patient may use weighing scales, asare well known.

The composition (e.g. pharmaceutical composition) may be for use fortreatment of infertility in a patient identified (prior to treatment) ashaving bodyweight <59 kg, for example <56 kg, for example <55 kg, forexample <52 kg, for example <50 kg, for example <45 kg, for example <42kg, for example <31.5 kg. The composition (e.g. pharmaceuticalcomposition) may be for use for treatment of infertility in a patientidentified (prior to treatment) as having bodyweight from 40 to 59.9 kg,for example for treatment of infertility in a patient having bodyweightfrom 45 to 55 kg. The composition may be for use for treatment ofinfertility in a patient identified (prior to treatment) as havingAMH≥16 pmol/L, for example AMH≥19 pmol/L, for example AMH≥26 pmol/L, forexample AMH≥28 pmol/L, for example AMH≥30 pmol/L, for example AMH≥40pmol/L.

Preferably, the composition (e.g. pharmaceutical composition) is for usefor treatment of infertility in a patient identified (prior totreatment) as having bodyweight <52 kg (for example <50 kg, for example<45 kg) and identified (prior to treatment) as having AMH≥26 pmol/L (forexample AMH≥28 pmol/L, for example AMH≥30 pmol/L, for example AMH≥40pmol/L). In this example the treatment of infertility may include a stepof identifying the patient (prior to treatment) based on the serum AMHlevel and bodyweight of the patient, and a step of administering thedose to the patient identified (prior to treatment) as having AMH≥26pmol/L, and identified (prior to treatment) as having bodyweight <52 kg.

Preferably the FSH is a recombinant FSH (rFSH). Preferably the rFSH(e.g. human cell line derived recombinant FSH) includes α2,3- andα2,6-sialylation. The FSH (rFSH) for use according to the invention mayhave 1% to 99% of the total sialylation being α2,3-sialylation. The FSH(rFSH) according to the invention may have 1% to 99% of the totalsialylation being α2,6-sialylation. Preferably, 80 to 95%, for example80 to 90%, for example 82 to 89%, for example 85 to 89% of the totalsialylation is α2,3-sialylation. Preferably 5 to 20%, for example 10 to20%, for example 11 to 18%, for example 11 to 15%, of the totalsialylation is α2,6-sialylation. By sialylation it is meant the amountof sialic residues present on the FSH carbohydrate structures.α2,3-sialylation means sialylation at the 2,3 position (as is well knownin the art) and α2,6 sialylation at the 2,6 position (also well known inthe art). Thus “% of the total sialylation may be α 2,3 sialylation”refers to the % of the total number of sialic acid residues present inthe FSH which are sialylated in the 2,3 position. The term “% of thetotal sialylation being α2,6-sialylation” refers to the % of the totalnumber of sialic acid residues present in the FSH which are sialylatedin the 2,6 position. The rFSH may be present as a single isoform or as amixture of isoforms.

The composition may be for use for treatment of infertility in an Asianpatient (e.g. Japanese, Chinese, Korean, Indian patient, for example apatient of Han, Yamato or Korean ethnicity).

According to the present invention in a further aspect there is provideda medicament for treatment of infertility in an Asian (e.g. Japanese,Chinese, Korean, Indian) patient comprising follicle stimulating hormone(FSH), preferably recombinant FSH; wherein the medicament isadministered to an Asian (e.g. Japanese, Chinese, Korean, Indian)patient identified (prior to treatment) as having serum AMH level of ≥15pmol/L (for example AMH≥16 pmol/L, for example AMH≥19 pmol/L, forexample AMH≥28 pmol/L) and identified (prior to treatment) as havingbodyweight less than 60 kg; and wherein the medicament is administeredat a daily dose of, or daily dose equivalent to, 6 to 8 μg recombinantFSH. Preferably, the daily dose is 6 to 8 μg recombinant FSH. Morepreferably, the daily dose is 6 μg recombinant FSH.

The treatment of infertility may include a step of identifying thepatient (prior to treatment) based on the serum AMH level and bodyweightof the patient. The treatment of infertility may include a step ofadministering the dose to the patient identified as having the definedserum AMH level and bodyweight. For example, the treatment ofinfertility may include a step of identifying the patient (prior totreatment) based on the serum AMH level and bodyweight of the patient,and a step of administering the dose to the patient identified (prior totreatment) as having AMH≥15 pmol/L (for example AMH≥16 pmol/L, forexample AMH≥19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28pmol/L, for example AMH≥40 pmol/L) and identified (prior to treatment)as having bodyweight <60 kg [e.g. bodyweight <55 kg, for example <52 kg,for example <50 kg, for example <45 kg].

The step of identifying the patient (prior to treatment) based on theserum AMH level and bodyweight of the patient may take place just before(e.g. 0 to 2 days before) the dose is first administered to the patient.The step of identifying the patient may be based on a serum AMH leveldetermined previously (e.g. a serum AMH level determined up to twelvemonths before the dose is first administered to the patient). Preferablythe serum AMH level of the patient is determined (measured) by theELECSYS AMH Plus immunoassay (available from Roche, of Switzerland, seewww.roche.com). The step of identifying the patient may be based on abodyweight of the patient determined just before (e.g. 0 to 2 daysbefore) the dose is first administered to the patient. The step ofdetermining the bodyweight of the patient may use weighing scales, asare well known.

Herein, “day one of treatment”, also referred to as “day one ofstimulation”, refers to the first day that the dose of (e.g.recombinant) FSH is administered to the patient. Day one of treatment(stimulation) may take place on day 1, 2 or 3, preferably day 2 or day3, of the patient's menstrual cycle. In other words, day one oftreatment (stimulation) may be one, two or three days, preferably two orthree days, after the patient commences menstrual bleeding, as is wellknown in the art.

The dose of FSH starts on day one of treatment and may continue for twoto twenty days, for example continue for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 days. The dose of FSH starts onday one of treatment and may continue for seven to thirteen days, forexample nine to thirteen days, for example 10 to 13 days, for example 10to 11 days. The dose of FSH may be administered at a dose equivalent tothe daily doses mentioned above. For example the composition may be foradministration at a dose of 18 μg FSH every three days (e.g. foradministration on days 1, 4, 7 and so on).

The composition (e.g. pharmaceutical composition) or medicament may beadministered after pre-treatment of the patient with a (different)pharmaceutical composition which suppresses endogenous gonadotropinproduction prior to day one of the treatment with FSH (e.g. after thesubject has been (pre-)treated with a steroid, a GnRH agonist, a GnRHantagonist etc.). Herein, the term “pre-treated” or “pre-treatment”refers to administration of the pharmaceutical composition whichsuppresses endogenous gonadotropin production prior to day one of thetreatment with FSH and hCG. This is well known in the art. Thus, thecomposition (e.g. pharmaceutical composition) or medicament may be foradministration 12 to 16, e.g. 13 to 15, e.g. 14 days afteradministration of (e.g. after initiation of administration of, e.g.after initiation of daily administration of) a GnRH agonist (e.g.Synarel, Lupron, Decapeptyl). The product may be for administration witha GnRH agonist.

In other examples, the composition (e.g. pharmaceutical composition) ormedicament may be for administration prior to administration of a GnRHantagonist (e.g. ganirelix, cetrorelix), for example for administrationfive or six days prior to administration of a GnRH antagonist. Theproduct may be for administration with a GnRH antagonist.

Preferably the composition (e.g. pharmaceutical composition) ormedicament is for administration prior to administration of a high(ovulatory) dose of hCG (for example 4,000 to 11,000 IU hCG, e.g. 5,000IU hCG, 10,000 IU hCG etc.; or 150 to 350 microgram recombinant hCG, forexample 250 microgram recombinant hCG) to induce final follicularmaturation.

The doses above may be for treatment of infertility in the patient's(subject's) first stimulation protocol. It will be appreciated that forfurther stimulation cycles, the doses may be adjusted according toactual ovarian response in the first cycle.

The applicants have devised “individualised” COS protocols whereinspecific doses of recombinant FSH having specific characteristics areused to treat patients based on their specific AMH levels, therebyincreasing the likelihood of adequate response to stimulation (e.g. inpatients having a low response potential), and/or decreased risk of OHSS(e.g. in patients classed as high or excessive responders).

The serum level of AMH may be determined (e.g. measured) by any methodknown in the art. The serum AMH level may be measured using the AMHGen-II enzyme linked immunosorbent assay, a kit (Beckman Coulter, Inc.,Webster, Tex.). This assay can detect AMH concentrations greater than0.57 pmol/L with a minimum limit of quantitation of 1.1 pmol/L. Theserum AMH level may be measured using the automated AMH ACCESS assay(Beckman Coulter, Inc., Webster, Tex.). Preferably, the serum AMH levelis measured using the Elecsys® AMH assay from Roche Diagnostics. Otherassays may be used.

Herein, serum AMH values are generally recited in terms of pmol/L. Thismay be converted to ng/mL using the conversion equation 1 ng/ml AMH=7.1pmol/L AMH.

Herein the terms “patient” and “subject” are used interchangeably.

Herein the term “treatment of infertility” includes treatment ofinfertility by controlled ovarian stimulation (COS) or methods whichinclude a step or stage of controlled ovarian stimulation (COS), forexample Intra Uterine Insemination (IUI), in vitro fertilisation (IVF),or intracytoplasmic sperm injection (ICSI). The term “treatment ofinfertility” includes treatment of infertility by ovulation induction(01) or by methods which include a step or stage of ovulation induction(01). The term “treatment of infertility” includes treatment ofinfertility in a subject having tubal or unexplained infertility,including treatment of infertility in a subject having endometriosis,for example stage I or stage II endometriosis, and/or in a subjecthaving anovulatory infertility, for example WHO type II anovulatoryinfertility, and/or in a subject with a partner with male factorinfertility. The product (or composition) may be for (use in) thetreatment of infertility (and/or for controlled ovarian stimulation) ina subject having endometriosis, for example in a subject having stage Ior stage II endometriosis, as defined by The American Society forReproductive Medicine (ASRM) classification system for the variousstages of endometriosis, (stage IV most severe; stage I least severe)[American Society for Reproductive Medicine. Revised American Societyfor Reproductive Medicine classification of endometriosis: 1996. FertilSteril 1997; 67,817 821.].

The composition or medicament may be for (use in) the treatment ofinfertility (and/or for controlled ovarian stimulation) in a subjecthaving normal serum FSH level of 1 to 16 IU/L, for example 1 to 12 IU/L,in the early follicular phase.

The composition or medicament may be for (use in) the treatment ofinfertility (and/or for controlled ovarian stimulation) in a subjectaged 18 to 42 years, for example 25 to 37 years. The product may be for(use in) the treatment of infertility (and/or for controlled ovarianstimulation) in a subject having BMI≥1 and BMI<35 kg/m², for example asubject having BMI≥18 and BMI<25 kg/m², for example a subject havingBMI≥20 and BMI<25 kg/m².

The rFSH may be produced or expressed in a human cell line, for examplea Per.C6 cell line, a HEK293 cell line, a HT1080 cell line etc. This maysimplify (and render more efficient) the production method becausemanipulation and control of e.g. the cell growth medium to retainsialylation may be less critical than with known processes. The methodmay also be more efficient because there is little basic rFSH producedcompared to production of known rFSH products; more acidic rFSH isproduced and separation/removal of basic FSH is less problematic. TherFSH may be produced or expressed in a PER.C6® cell line, a PER.C6®derived cell line or a modified PER.C6® cell line. rFSH which isproduced or expressed in a human cell line (e.g. PER.C6® cell line,HEK293 cell line, HT1080 cell line etc.) will include some α2,6-linkedsialic acids (α2,6 sialylation) provided by endogenous sialyltransferase activity [of the cell line] and will include someα2,3-linked sialic acids (α2,3 sialylation) provided by endogenoussialyl transferase activity. The cell line may be modified usingα2,3-sialyltransferase. The cell line may be modified usingα2,6-sialyltransferase. Alternatively or additionally, the rFSH mayinclude α2,6-linked sialic acids (a2,6 sialylation) provided byendogenous sialyl transferase activity [of the cell line]. Herein, theterm “human derived recombinant FSH” means recombinant FSH which isproduced or expressed in a human cell line (e.g. recombinant FSH made byengineering a human cell line).

The rFSH may be produced using α2,3- and/or α2,6-sialyltransferase. Inan example, rFSH is produced using α2,3-sialyltransferase. The rFSH mayinclude α2,6-linked sialic acids (α2,6 sialylation) provided byendogenous sialyl transferase activity.

The composition may be a pharmaceutical composition. The pharmaceuticalcomposition is for the treatment of infertility. The treatment ofinfertility may comprise assisted reproductive technologies (ART),ovulation induction or intrauterine insemination (IUI). Thepharmaceutical composition may be used, for example, in medicalindications where known FSH preparations are used.

The composition or medicament can be formulated into well-knowncompositions for any route of drug administration, e.g. oral, rectal,parenteral, transdermal (e.g. patch technology), intravenous,intramuscular, subcutaneous, intrasusternal, intravaginal,intraperitoneal, local (powders, ointments or drops) or as a buccal ornasal spray. A typical composition comprises a pharmaceuticallyacceptable carrier, such as aqueous solution, non toxic excipients,including salts and preservatives, buffers and the like, as described inRemington's Pharmaceutical Sciences fifteenth edition (Matt PublishingCompany, 1975), at pages 1405 to 1412 and 1461-87, and the nationalformulary XIV fourteenth edition (American Pharmaceutical Association,1975), among others.

Examples of suitable aqueous and non-aqueous pharmaceutical carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol, and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.The compositions or medicaments of the present invention also cancontain additives such as but not limited to preservatives, wettingagents, emulsifying agents, surfactants and dispersing agents.Antibacterial and antifungal agents can be included to prevent growth ofmicrobes and includes, for example, m-cresol, benzyl alcohol, paraben,chlorobutanol, phenol, sorbic acid, and the like. If a preservative isincluded, benzyl alcohol, phenol and/or m-cresol are preferred; however,the preservative is by no means limited to these examples. Furthermore,it may be desirable to include isotonic agents such as sugars, sodiumchloride, and the like.

The composition or medicament may further comprise a salt comprising apharmaceutically acceptable alkali metal cation selected from the groupconsisting of Na⁺- or K⁺-salts, or a combination thereof. Preferably thesalt is a Na⁺-salt, for example NaCl or Na₂SO₄.

Preferably the composition or medicament comprises recombinant FSH andone or more of Polysorbate 20, L-methionine, phenol, disodium sulphateand sodium phosphate buffer.

In some cases, to effect prolonged action it is desirable to slow theabsorption of FSH (and other active ingredients, if present) fromsubcutaneous or intramuscular injection. This can be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of FSH then depends uponits rate of dissolution which, in turn, can depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered FSH combination form is accomplished by dissolving orsuspending the FSH combination in an oil vehicle. Injectable depot formscan be made by forming microencapsule matrices of the FSH (and otheragents, if present) in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of FSH to polymerand the nature of the particular polymer employed, the rate of FSHrelease can be controlled. Examples of other biodegradable polymersinclude polyvinylpyrrolidone, poly(orthoesters), poly(anhydrides) etc.Depot injectable formulations are also prepared by entrapping the FSH inliposomes or microemulsions which are compatible with body tissues.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium justprior to use. Injectable formulations can be supplied in any suitablecontainer, e.g. vial, pre-filled syringe, injection cartridges, and thelike.

The composition or medicament may be formulated for single use or formultiple use (multiple dose). If the composition or medicament isformulated for multiple use, it is preferred that a preservative isincluded. If a preservative is included, benzyl alcohol, phenol and/orm-cresol are preferred; however, the preservative is by no means limitedto these examples. The single use or multiple use formulated compositionor medicament may further comprise a salt comprising a pharmaceuticallyacceptable alkali metal cation selected from the group consisting ofNa⁺- or K⁺-salts, or a combination thereof. Preferably the salt is aNa⁺-salt, for example NaCl or Na₂SO₄.

The composition or medicament may be included in a container such as avial, prefilled cartridge (e.g. for single administration or multipleuse) or an injection device such as a “pen” for e.g. administration ofmultiple doses.

The composition or medicament may be a formulation (e.g. injectableformulation) including FSH (optionally with hCG, LH, LH activity etc.)The LH activity, if present, may originate from LH or human chorionicgonadotropin, hCG. If there is more than one active ingredient (i.e. FSHand e.g. hCG or LH) these may be suitable for administration separatelyor together. If administered separately, administration can besequential. The composition or medicament can be supplied in anyappropriate package. For example, a composition or medicament caninclude a number of containers (e.g. pre-filled syringes or vials)containing either FSH or hCG, or a combination (or combination) of bothFSH and hCG. The hCG may be recombinant hCG or urinary hCG. If thecomposition or medicament includes a number of containers (e.g.pre-filled syringes or vials) containing FSH, e.g. recombinant FSH, eachcontainer may include the same amount of FSH. One or more containers mayinclude different amounts of FSH. The syringes or vials may be packagedin a blister package or other means to maintain sterility. Anycomposition or medicament can optionally contain instructions for usingthe FSH (and e.g. hCG if present) formulations. The pH and exactconcentration of the various components of the pharmaceuticalcomposition are adjusted in accordance with routine practice in thisfield. See GOODMAN and GILMAN's THE PHARMACOLOGICAL BASIS FORTHERAPEUTICES, 7th ed. In a preferred embodiment, the composition ormedicament of the invention are supplied as compositions for parenteraladministration. General methods for the preparation of the parenteralformulations are known in the art and are described in REMINGTON; THESCIENCE AND PRACTICE OF PHARMACY, supra, at pages 780-820. Theparenteral compositions can be supplied in liquid formulation or as asolid which will be mixed with a sterile injectable medium just prior toadministration. In an especially preferred embodiment, the parenteralcompositions are supplied in dosage unit form for ease of administrationand uniformity of dosage.

According to the present invention in a further aspect there is provideda method of treatment of infertility comprising: a step of administeringa daily dose of, or a daily dose equivalent to, 6 to 8 μg recombinantFSH, to a patient (e.g. a female patient) having AMH 15 pmol/L (forexample AMH≥16 pmol/L, for example AMH≥19 pmol/L, for example AMH≥26pmol/L, for example AMH≥28 pmol/L, for example AMH≥40 pmol/L) andbodyweight <60 kg [e.g. bodyweight <55 kg, for example <52 kg, forexample <50 kg, for example <45 kg, for example <42 kg, for example<31.5 kg]. Preferably, the daily dose is 6 to 8 μg recombinant FSH. Morepreferably, the daily dose is 6 μg recombinant FSH.

The method may include a step of determining the serum AMH level andbodyweight of the patient. The method may include a step ofadministering the dose to the patient having the defined serum AMH leveland bodyweight. For example, the method may include a step ofdetermining the serum AMH level and bodyweight of the patient, and astep of administering the dose to the patient having AMH≥15 pmol/L (forexample AMH≥16 pmol/L, for example AMH 19 pmol/L, for example AMH≥26pmol/L, for example AMH≥28 pmol/L, for example AMH≥40 pmol/L) andbodyweight <60 kg (e.g. bodyweight <55 kg, for example <52 kg, forexample <50 kg, for example <45 kg, for example <42 kg, for example<31.5 kg).

According to the present invention in a further aspect there is provideda method of treatment of infertility comprising a step of administeringa daily dose of, or a daily dose equivalent to, 6 to 8 μg recombinantFSH to a patient (e.g. a female patient) identified (prior to treatment)as having AMH≥15 pmol/L (for example AMH≥16 pmol/L, for example AMH≥19pmol/L, for example AMH≥26 pmol/L, for example AMH≥28 pmol/L, forexample AMH≥40 pmol/L) and identified (prior to treatment) as havingbodyweight <60 kg (e.g. bodyweight <55 kg, for example <52 kg, forexample <50 kg, for example <45 kg). Preferably, the daily dose is 6 to8 μg recombinant FSH. More preferably, the daily dose is 6 μgrecombinant FSH.

The method may include a step of identifying the patient (prior totreatment) based on the serum AMH level and bodyweight of the patient.The method may include a step of administering the dose to a patientidentified as having the defined serum AMH level and bodyweight. Forexample, the method may include a step of identifying the patient (priorto treatment) based on the serum AMH level and bodyweight of thepatient, and a step of administering the dose to the patient identified(prior to treatment) as having AMH≥15 pmol/L (for example AMH≥16 pmol/L,for example AMH≥19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28pmol/L, for example AMH≥40 pmol/L) and identified (prior to treatment)as having bodyweight <60 kg [e.g. bodyweight <55 kg, for example <52 kg,for example <50 kg, for example <45 kg].

The method may be for use for treatment of infertility in an Asian (e.g.Japanese, Chinese, Korean, Indian) patient.

Preferably, the patient has (is identified as having) bodyweight <52 kg(for example <50 kg, for example <45 kg) and has (is identified ashaving) AMH≥26 pmol/L (for example AMH≥28 pmol/L, for example AMH≥30pmol/L, for example AMH≥40 pmol/L).

Preferably the FSH is a recombinant FSH (rFSH). Preferably the rFSH(e.g. human cell line derived recombinant FSH) includes α2,3- andα2,6-sialylation. The FSH (rFSH) for use according to the invention mayhave 1% to 99% of the total sialylation being α2,3-sialylation. The FSH(rFSH) according to the invention may have 1% to 99% of the totalsialylation being α2,6-sialylation. Preferably, 80 to 95%, for example80 to 90%, for example 82 to 89%, for example 85 to 89% of the totalsialylation is α2,3-sialylation. Preferably 5 to 20%, for example 10 to20%, for example 11 to 18%, for example 11 to 15%, of the totalsialylation is α2,6-sialylation. By sialylation it is meant the amountof sialic residues present on the FSH carbohydrate structures.α2,3-sialylation means sialylation at the 2,3 position (as is well knownin the art) and α2,6 sialylation at the 2,6 position (also well known inthe art). Thus “% of the total sialylation may be a 2,3 sialylation”refers to the % of the total number of sialic acid residues present inthe FSH which are sialylated in the 2,3 position. The term “% of thetotal sialylation being α2,6-sialylation” refers to the % of the totalnumber of sialic acid residues present in the FSH which are sialylatedin the 2,6 position. The rFSH may be present as a single isoform or as amixture of isoforms.

According to the present invention in an aspect there is provided acomposition for use in the treatment of infertility in a patient havingAMH≥26 pmol/L and bodyweight <52 kg, the composition comprising a dailydose of 6 to 8 μg recombinant FSH. Preferably, the patient has (isidentified as having) bodyweight <52 kg (for example <50 kg, for example<45 kg) and has (is identified as having) AMH≥26 pmol/L (for exampleAMH≥28 pmol/L, for example AMH≥30 pmol/L, for example AMH≥40 pmol/L).

According to the present invention in another aspect there is provided acomposition for use in the treatment of infertility in a patient havingAMH≥26 pmol/L and bodyweight <61 kg, the composition comprising a dailydose of, or a daily dose equivalent to, 6 to 8 μg recombinant FSH.Preferably, the patient has (is identified as having) bodyweight <52 kg(for example <50 kg, for example <45 kg) and has (is identified ashaving) AMH≥26 pmol/L (for example AMH 28 pmol/L, for example AMH≥30pmol/L, for example AMH≥40 pmol/L).

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in more detail withreference to the following examples and FIG. 1 which presents the bodyweight and AMH of all patients in the Japanese Phase II clinical trialdiscussed in the retrospective analysis of Example 3, and indicateswhether the dose protocol set out in Table A above would specify a doseof <6 μg Rekovelle® (diamonds) or ≥6 μg Rekovelle.

Example 1—Rekovelle

Rekovelle® is a recombinant FSH expressed in a PER.C6® cell lineengineered by the methods disclosed in WO2013/020996 and WO2009/127826A.

The Marketing Authorisation holder for Rekovelle® is FerringPharmaceuticals NS of Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark,and it is available in the UK from Ferring Pharmaceuticals of DraytonHall, Church Road, West Drayton, UB7 7PS, UK

The active substance in Rekovelle® is follitropin delta (FE999049).Rekovelle is highly sialylated and includes α2,3- and α2,6-sialylation,with about 85% to 90% of the total sialylation being α2,3-sialylationand about 10% to 15% of the total sialylation being α2,6-sialylation.

REKOVELLE is a clear and colourless solution for injection (injection).It is available in packs of 1 cartridge and 3 pen injection needles.Each multidose cartridge contains 12 micrograms of follitropin delta in0.36 millilitre of solution. One millilitre of solution contains 33.3micrograms of follitropin delta in each millilitre of solution. Theother ingredients are phenol, polysorbate 20, L-methionine, sodiumsulphate decahydrate, disodium phosphate dodecahydrate, concentratedphosphoric acid, sodium hydroxide and water for injections.

Example 2—a Randomised, Assessor-Blind, (AMH)-Stratified, Dose ResponseTrial in Japanese IVF/ICSI Patients Undergoing Controlled OvarianStimulation with Follitropin Delta

A randomised, controlled, assessor-blind, parallel groups, multi-centrephase 2 anti-Müllerian hormone (AMH)-stratified trials was conducted inIVF/ICSI patients in Japan, with the purpose of determining thedose-response relationship of FE 999049 and the number of oocytesretrieved. Randomisation was stratified according to AMH levels atscreening; low AMH (5.0-14.9 pmol/L) or high AMH (15.0-44.9 pmol/L).

There were 158 patients, 20 to 39 years (mean age 33.7 years) undergoingCOS with three dose levels of FE 999049, follitropin delta (FerringPharmaceuticals). The doses of FE 999049 were 6 μg/day, 9 μg/day and 12μg/day and a standard therapy of the approved rFSH product (FOLLISTIM,MSD, 150 IU/day) was also included as control. At present, follitropinbeta (FOLLISTIM) is the only medicinal product approved in Japan forcontrolled ovarian stimulation in IVF/ICSI cycles.

Patients were randomised to fixed doses of 6 μg/day, 9 μg/day and 12μg/day FE 999049 (n=117) or 150 IU follitropin beta (n=41).Randomisation was stratified according to AMH level [low AMH=5.0-14.9pmol/L; high AMH=15.0 to 44.9 pmol/L; Elecsys AMH, Roche Diagnostics).Gonadotropin ws initiated on day 2-3 of the menstrual cycle. Ganrelix0.25 mg/day added from day 6 of stimulation and triggering of finalfollicular maturation was done on the day when ≥3 follicles with adiameter ≥17 mm are observed. OHSS was assessed using Golan'sclassification.

The daily dose was fixed throughout the stimulation period. Astatistically significant dose response relationship for FE 999049 withrespect to the number of oocytes retrieved was observed for the overallpopulation and for each AMH randomisation stratum. Acceptable pregnancyrates were achieved with all FE 999049 doses.

Patients were not dosed by body weight in this trial and no patientreceived a dose below 6 μg/day FE 999049. No patient in this trial wasidentified prior to treatment by combination of AMH and bodyweight.

Example 3 Retro-Analysis of Phase II Trial

In many Asian countries (for example Japan, China, South Korea andIndia), many women have a low body weight, compared to women in the USand Western Europe. There is therefore a risk that administering a fixeddose, suitable for the general population in Europe, to Asian/Japanesepatients, could lead to low body-weight patients receiving a dose of FSHwhich is high in terms of dose/kg body weight. This in turn could leadto risk of over-response and OHSS in these patients. The traditional“fixed dose” FSH protocols may be a factor in some high reported OHSSrates in Japanese studies.

The dose protocol set out in Table A above goes some way to mitigatingthis risk because patients are dosed by bodyweight. However, very lowdoses of gonadotropins are potentially associated with inadequatefollicular recruitment and poor ovarian response. There is therefore arisk that dosing according to the Table A protocol might lead to verylight patients with high AMH receiving a dose of FSH which may besub-optimal from an efficacy perspective. There is therefore a need foreffective dosing of lighter patients (weight <60 kg) with high AMH whilereducing risk of overstimulation and OHSS in these patients (who may bemore prone to this risk because they have high AMH and low bodyweight).

Overall in the Japanese phase 2 trial, there were no safety concernswith the FE 999049 dose of 6 μg. The safety profile of patients in theJapanese phase 2 trial who had a body weight <60 kg has beeninvestigated retrospectively. As context to the observations in the 6 μgFE 999049 group, the data from the reference therapy group withFOLLISTIM are also displayed. Table 1 displays safety parametersrelevant to ovarian response.

TABLE 1 Comparison of Ovarian Response Safety Parameters for Subjects<60 kg exposed to 6 μg FE 999049 or 150 IU FOLLISTIM - overall FE 999049FOLLISTIM 6 ug 150 IU (N = 29) (N = 33) n % n % Early OHSS 4 13.8% 824.2% Early Moderate/Severe OHSS 3 10.3% 7 21.2% GnRH agonist triggering1 3.0% 15-19 oocytes retrieved 1 3.4% 5 15.2% >=20 oocytes retrieved 26.1%

Among patients with a body weight <60 kg, the total number of patientswith early OHSS was 4 (13.8%) in the 6 μg FE 999049 group and 8 (24.2%)in the 150 IU FOLLISTIM group. Early moderate/severe OHSS was reportedfor 3 (10.3%) patients and 7 (21.2%) patients in the 6 μg FE 999049 and150 IU FOLLISTIM groups, respectively. Furthermore, oocyte yield abovethe appropriate response of 8-14 oocytes was only observed in 1 (3.4%)patient in the 6 μg FE 999049 group in contrast to 7 (21.2%) patients inthe 150 IU FOLLISTIM group. Excessive follicular development to theextent that GnRH agonist triggering was required was not observed in anypatients in the 6 μg FE 999049 group, but did occur for 1 patient in the150 IU FOLLISTIM group. Thus, the safety ovarian response profile inpatients weighing <60 kg seems to be improved with 6 μg FE 999049compared to 150 IU FOLLISTIM.

Table 1 covers all patients with body weight <60 kg, independent of AMHlevel. All patients with AMH<15 pmol/L will receive 12 μg FE 999049. Thesituation where a patient may have a calculated dose <6 μg but willreceive 6 μg is therefore only applicable to patients with AMH≥15pmol/L. Data on patients in the Japanese phase 2 trial who had bodyweight <60 kg and AMH≥15 pmol/L are presented in Table 2.

TABLE 2 Comparison of Ovarian Response Safety Parameters for Subjects<60 kg exposed to 6 μg FE 999049 or 150 IU FOLLISTIM - High AMH StratumFE 999049 FOLLISTIM 6 ug 150 IU (N = 18) (N = 22) n % n % Early OHSS 422.2% 7 31.8% Early Moderate/Severe OHSS 3 16.7% 6 27.3% GnRH agonisttriggering 1 4.5% 15-19 oocytes retrieved 1 5.6% 4 18.2% >=20 oocytesretrieved 2 9.1%

Among the patients with a body weight <60 kg and AMH≥15 pmol/L, thetotal number of patients with early OHSS was 4 (22.2%) in the 6 μg FE999049 group and 7 (31.8%) in the 150 IU FOLLISTIM group.Moderate/severe OHSS was the most common severity among the early OHSScases and was reported for 3 (16.7%) patients in the 6 μg FE 999049group and 6 (27.3%) patients in the 150 IU FOLLISTIM group. While only 1(5.6%) patient in the 6 μg FE 999049 group had 15-19 oocytes retrieved,this was the case of 4 (18.2%) patients in the 150 IU FOLLISTIM groupwhere additionally 2 (9.1%) patients had ≥20 oocytes. Triggering withGnRH agonist due to excessive follicular development was not needed inthe 6 μg FE 999049 group but was needed for 1 patient in the 150 IUFOLLISTIM group. Thus, controlled ovarian stimulation with 6 μg FE999049 in patients weighing <60 kg and with AMH≥15 pmol/L was associatedwith less risk of early OHSS and less risk of excessive ovarian responsethan controlled ovarian stimulation with 150 IU FOLLISTIM.

Concerning the adverse event profile in patients with a body weight <60kg, the frequency of adverse events judged by the investigator to berelated to the drug used for controlled ovarian stimulation was 20.7% inthe 6 μg FE 999049 group and 33.3% in the 150 IU FOLLISTIM group. Amongthe patients with body weight <60 kg and AMH≥15 pmol/L, the frequency ofrelated adverse events was 27.8% in the 6 μg FE 999049 group and 36.4%in the 150 IU FOLLISTIM group.

From an efficacy perspective, the clinical pregnancy rate per cycle withtransfer in patients with body weight <60 kg was 40.0% in the 6 μg FE999049 group and 21.7% in the standard therapy group. For patients withbody weight <60 kg and AMH≥15 pmol/L, the clinical pregnancy rate percycle with transfer was 38.5% and 20.0% in the 6 μg FE 999049 andstandard therapy groups, respectively.

Finally, Ferring identified the patients in the Japanese phase 2 trialwho based on AMH and body weight would have received <6 μg FE 999049according to the individualised FE 999049 dosing regimen (Table Aabove), but in this trial received either 6 μg FE 999049 or 150 IUFOLLISTIM as per randomisation. This was only a very limited number ofpatients (5 patients in the 6 μg FE 999049 group, and 3 patients in the150 IU FOLLISTIM group), but the ovarian response safety data were inline with those presented earlier. Ovarian response of 15 oocytes ormore was not observed in any of the 5 patients in the 6 μg FE 999049group but in 2 of 3 patients (66.7%) in the 150 IU FOLLISTIM group.Excessive follicular development requiring triggering with GnRH agonistwas not observed in any of the 5 patients in the 6 μg FE 999049 groupbut in 1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group. Early OHSSwas reported for 1 of 5 patients (20.0%) in the 6 μg FE 999049 group andfor 1 of 3 patients (33.3%) in the 150 IU FOLLISTIM group.

In other words, the applicants surprisingly found that it is possible tospecify a minimum dose of 6 μg to account for the lower body weight inthe Japanese population, with the intention of avoiding underdosing ofJapanese patients with low body weight, and thereby maintain efficacy inthese patients, while avoiding side effects such as OHSS.

In addition to the safety and efficacy data with 6 μg FE 999049 in theJapanese phase 2 trial supporting the appropriateness of this dose,simulations have been conducted using the dose-response model that hasbeen estimated from the Japanese phase 2 trial. The purpose of thesesimulations is to evaluate the expected difference in the number ofoocytes with the proposed dosing regimen with 6 μg as the lowest dosecompared to a dosing regimen with doses allowed to be <6 μg. Based onthe body weight and AMH levels of all 158 randomised patients in theJapanese phase 2 trial, 18 (11%) would receive with the proposed dosingregimen a dose of 6 μg instead of a calculated dose <6 μg. All of thesepatients had a body weight below 52 kg and an AMH exceeding 26 pmol/L,as illustrated in FIG. 1, which presents the body weight and AMH of allpatients in the trial. FIG. 1 shows these 18 patients with smalldiamonds (rather than squares) to the bottom right of the figure.

In the 18 patients with a calculated dose <6 μg, the mean calculateddose is 5.33 μg and the proposed dosing regimen amounts thus to a 13%higher mean dose compared to the regimen without a minimum (mean dose6.0 μg instead of 5.33 μg).

The ovarian response is expected to be beneficially influenced byimplementing 6 μg as the minimum dose. In patients with a calculateddose <6 μg, more patients are anticipated to achieve the target of 8-14oocytes retrieved with the proposed dosing regimen where 6 μg is theminimum dose (48.0% of patients, versus 44.8% with the regimen without aminimum dose), as shown in Table 3.

TABLE 3 Predicted outcome in Japanese patients with calculated dose <6μg FE 999049 No minimum Minimum Treatment outcome dose dose of for FE999049 established 6 μg Difference Patients with 8-14 44.8% 48.0% +3.2%oocytes retrieved

Thus, in addition to the observed data from the Japanese phase 2 trial,model predictions of the ovarian response with the proposed dosingregimen further support the appropriateness of a minimum dose of 6 μg.

In conclusion, the proposed FE 999049 dosing regimen, including theimplementation of 6 μg as the minimum dose, is safe and efficacious, andis proposing this for the phase 3 trial in Japan. Phase 3 data onJapanese patients with a calculated dose <6 μg will be analysedspecifically for the purpose of PMDA review to support the efficacy andsafety of 6 μg FE 999049 in these patients.

Example 10—Phase 3 Clinical Trial in Japan Methodology

This will be a randomised, assessor-blind, controlled, parallel groups,multicentre trial assessing the efficacy and safety of FE 999049 in itsindividualised dosing regimen when used in first cycle Japanese patientsaged 20-40 years undergoing controlled ovarian stimulation for IVF/ICSIfollowing a gonadotropin-releasing hormone (GnRH) antagonist protocol.The trial has been designed to demonstrate non-inferiority of FE 999049versus an rFSH product approved in Japan, i.e. FOLLISTIM, with respectto number of oocytes retrieved.

Subjects will be screened within 60 days prior to start of stimulationfor compliance with the inclusion and exclusion criteria. On day 2-3 ofthe menstrual cycle, subjects will be randomised in a 1:1 ratio tocontrolled ovarian stimulation with FE 999049 or FOLLISTIM.Randomisation will be stratified by centre and according to AMH levelsat screening (<15 pmol/L and ≥15 pmol/L).

Subjects randomised to FE 999049 will have their individual FE 999049dose determined on the basis of their AMH level at screening and theirbody weight at start of stimulation (see below). The daily FE 999049dose will be fixed throughout the stimulation period. For subjects withAMH<15 pmol/L, the daily FE 999049 dose is 12 μg, irrespective of bodyweight. For subjects with AMH≥15 pmol/L the daily FE 999049 dose is on acontinuous scale ranging from 0.19 to 0.10 μg/kg, i.e. dependent onactual AMH and body weight. This is set out in the Table below. Theminimum allowed daily FE 999049 dose is 6 μg and the maximum alloweddaily FE 999049 dose is 12 μg. Subjects can be treated with FE 999049for a maximum of 20 days, and coasting is not allowed.

For subjects randomised to FOLLISTIM, the dosing regimen is withinlabelling (see below). The starting dose of FOLLISTIM is 150 IU andfixed for the first five stimulation days after which it may be adjustedby 75 IU based on the individual response. The maximum daily FOLLISTIMdose allowed is 375 IU. Subjects can be treated with FOLLISTIM for amaximum of 20 days, and coasting is not allowed.

During stimulation, subjects will be monitored by transvaginalultrasound on stimulation day 1 and 6 and hereafter at least everysecond day. When 3 follicles of ≥15 mm are observed, visits must beperformed daily. To prevent a premature luteinising hormone (LH) surge,a GnRH antagonist will be initiated on stimulation day 6 at a daily doseof 0.25 mg and continued throughout the stimulation period. Triggeringof final follicular maturation will be done with 5,000 IU urinary humanchorionic gonadotropin (hCG) on the day when ≥3 follicles with adiameter ≥17 mm are observed. In case of excessive folliculardevelopment, defined as ≥25 follicles with a diameter ≥12 mm, the cycleshould be cancelled (note: in case of 25-35 follicles with a diametermm, a GnRH agonist may be administered as triggering for finalfollicular maturation). In case of poor follicular development, definedas the investigator judging that ≥3 follicles with a diameter ≥17 mmcannot be reached by day 20, the cycle is to be cancelled.

Oocyte retrieval will take place 36h (±2h) after triggering of finalfollicular maturation and the oocytes can be inseminated by IVF or ICSI.Fertilisation and embryo development will be assessed from oocyteretrieval to the day of transfer. One blastocyst of the best qualityavailable will be transferred on day 5 after oocyte retrieval whileremaining blastocysts may be cryopreserved. For subjects who underwenttriggering of final follicular maturation with GnRH agonist, no transferwill take place and blastocysts may instead be cryopreserved on day 5.All cryopreserved blastocysts can be used by the subject aftercompletion of the trial, in accordance with the declaration by JapanSociety of Obstetrics and Gynaecology (JSOG).

Vaginal progesterone tablets (LUTINUS, Ferring Pharmaceuticals) 100 mgthree times daily will be provided for luteal phase support from the dayafter oocyte retrieval until the day of the clinical pregnancy visit.Luteal phase support will only be provided to subjects planned toundergo transfer and can be terminated earlier in case of no transfer ora negative β3hCG test. A β3hCG test is performed 13-15 days aftertransfer followed by a transvaginal ultrasound 5-6 weeks after transferto assess clinical and vital pregnancy.

Blood samples will be collected during the trial for the purpose ofevaluating the endocrine profile as well as clinical chemistry andhaematology parameters. Endocrine parameters are measured at screening,stimulation day 1, stimulation day 6 and end-of-stimulation. Clinicalchemistry and haematology parameters are assessed at screening,end-of-stimulation and end-of-trial. Local tolerability of FE 999049following subcutaneous administration will be assessed by the subjectsthree times daily: immediately, 30 minutes and 24 hours after theinjection. The assessment of injection site reactions will be madethroughout the stimulation period and recorded by the subjects in adiary.

If trial procedures and/or assessments are to be performed on Sundays,public holidays or outside the opening hours of the clinic, theprocedures and/or assessments can be postponed to the upcoming weekday(maximum one day after original visit schedule) or cancelled, ifappropriate.

As obligatory follow-up, pregnancy progress and outcome data will begathered for subjects with a vital pregnancy. Data will be collected onongoing pregnancy (10-11 weeks after transfer) and pregnancy outcome aswell as neonatal health at birth and at 4 weeks after birth. Thepregnancy follow-up does not include any interventions but only datacollection. The pregnancy follow-up data will be based on reportsobtained from the subject's gynaecologist/obstetrician and the subject'sMaternal and Child Health Handbook. The data will be retrieved by thetrial site, either via the subject's gynaecologist/obstetrician, thesubject herself, or other sources, as applicable. Ferring intends tosubmit the J-NDA following completion of the main part of the trial(i.e. up to the clinical pregnancy visit), and to include the pregnancyfollow-up data available at that time in the J-NDA. The pregnancyfollow-up data can be submitted after completion.

Number of Subjects

Approximately 328 subjects will be randomised in a 1:1 ratio to FE999049 and FOLLISTIM.

Criteria for Inclusion/Exclusion

Women eligible for IVF and/or ICSI treatment, undergoing their firstIVF/ICSI cycle and diagnosed with tubal infertility, unexplainedinfertility, infertility related to endometriosis stage I/II or withpartners diagnosed with male factor infertility, will be included inthis trial. Subjects will be 20-40 years of age, with a body mass index(BMI) of 17.5-32.0 kg/m2.Women with endometriosis stage III/IV, history of recurrent miscarriageor with contraindications to controlled ovarian stimulation withgonadotropins will be excluded from participation in this trial.The complete list of inclusion and exclusion criteria is provided below.

Inclusion Criteria

1. Informed Consent Documents signed prior to any trial-relatedprocedures.2. In good physical and mental health.3. Japanese females between the ages of 20 and 40 years. The subjectsmust be at least 20 years (including the 20th birthday) when they signthe Informed Consent Documents and no more than 40 years (up to the daybefore the 41st birthday) at the time of randomisation.4. Infertile women diagnosed with tubal infertility, unexplainedinfertility, endometriosis stage I/II (defined by the revised AmericanSociety for Reproductive Medicine (ASRM) classification) or withpartners diagnosed with male factor infertility, eligible for in vitrofertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI)treatment using ejaculated sperm from male partner.5. Infertility for at least 1 year before randomisation (not applicablein case of tubal or severe male factor infertility).6. The trial cycle will be the subject's first controlled ovarianstimulation cycle for IVF/ICSI.7. Regular menstrual cycles of 24-35 days (both inclusive), presumed tobe ovulatory.8. Hysterosalpingography, hysteroscopy, saline infusion sonography ortransvaginal ultrasound documenting a uterus consistent with expectednormal function (e.g. no evidence of clinically interfering uterinefibroids defined as submucous or intramural fibroids larger than 3 cm indiameter, no polyps and no congenital structural abnormalities which areassociated with a reduced chance of pregnancy) within 1 year prior toscreening. This also includes women who have been diagnosed with any ofthe above medical conditions but have had them surgically correctedwithin 1 year prior to screening.9. Transvaginal ultrasound documenting presence and adequatevisualisation of both ovaries, without evidence of significantabnormality (e.g. no endometrioma greater than 3 cm or enlarged ovarieswhich would contraindicate the use of gonadotropins) and fallopian tubesand surrounding tissue without evidence of significant abnormality (e.g.no hydrosalpinx) within 1 year prior to screening. Both ovaries must beaccessible for oocyte retrieval.10. Early follicular phase (cycle day 2-4) serum levels of FSH between 1and 15 IU/L (results obtained within 3 months prior to screening).11. Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis CVirus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within1 year prior to screening.12. Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive)at screening.13. Willing to accept transfer of one blastocyst.

Exclusion Criteria

1. Known endometriosis stage III-IV (defined by the revised ASRMclassification).2. One or more follicles >10 mm (including cysts) observed on thetransvaginal ultrasound prior to start of stimulation on stimulation day1 (puncture of cysts prior randomisation is allowed).3. Known history of recurrent miscarriage (defined as three consecutivelosses after ultrasound confirmation of pregnancy (excl. ectopicpregnancy) and before week 24 of pregnancy).4. Known abnormal karyotype of subject or of her partner. In case thesperm production is severely impaired (concentration <1 million/mL),normal karyotype, including no Y-chromosome microdeletion, must bedocumented.5. Active arterial or venous thromboembolism or severe thrombophlebitis,or a history of these events.6. Known porphyria.7. Any known clinically significant systemic disease (e.g.insulin-dependent diabetes).8. Known inherited or acquired thrombophilia disease.9. Any known endocrine or metabolic abnormalities (pituitary, adrenal,pancreas, liver or kidney) which can compromise participation in thetrial with the exception of controlled thyroid function disease.10. Known presence of anti-FSH antibodies (based on the informationavailable in the subject's medical records).11. Known tumours of the ovary, breast, uterus, adrenal gland, pituitaryor hypothalamus which would contraindicate the use of gonadotropins.12. Any abnormal finding of clinical chemistry, haematology or vitalsigns at screening, which is judged clinically relevant by theinvestigator.13. Known moderate or severe impairment of renal or hepatic function.14. Currently breast-feeding.15. Undiagnosed vaginal bleeding.16. Known abnormal cervical cytology of clinical significance observedwithin 3 years prior to screening (unless the clinical significance hasbeen resolved).17. Findings from the laboratory analyses at screening which precludegonadotropin stimulation.18. Findings at the gynaecological examination at screening whichpreclude gonadotropin stimulation.19. Findings at the gynaecological examination at screening which areassociated with a reduced chance of pregnancy, e.g. congenital uterineabnormalities or retained intrauterine device.20. Pregnancy (must be confirmed by negative urinary pregnancy tests atscreening and prior to randomisation) or contraindication to pregnancy.21. Known current active pelvic inflammatory disease.22. Use of hormonal preparations (except for thyroid medication) orfertility modifiers during the last menstrual cycle before screening,including dehydroepiandrosterone (DHEA), metformin and cycle programmingwith oral contraceptives, progestogen or oestrogen preparations.23. Known history of chemotherapy (except for gestational conditions) orradiotherapy.24. Current or past (1 year prior to randomisation) abuse of alcohol ordrugs, and/or current (last month) intake of more than 14 units ofalcohol per week.25. Current or past (3 months prior to randomisation) smoking habit ofmore than 10 cigarettes per day.26. Hypersensitivity to any drug substance or excipients in themedicinal products used in the trial.27. Hypersensitivity to any drug substance or excipients in a GnRH orany GnRH analogue/derivative. 28. Previous participation in the trial.29. Current participation in another trial, including follow-up period.30. Use of any non-registered investigational drugs during the last 3months prior to screening.

On day 2-3 of the menstrual cycle, subjects will be randomised in a 1:1ratio to treatment with either FE 999049 or FOLLISTIM, and controlledovarian stimulation will be initiated.

FE 999049 Dosing Regimen

Subjects randomised to FE 999049 will have their individual dosedetermined on the basis of their AMH level at screening and their bodyweight at randomisation. For subjects with AMH<15 pmol/L the daily FE999049 dose is 12 μg, irrespective of body weight. For subjects withAMH≥15 pmol/L the daily FE 999049 dose is on a continuous scale rangingfrom 0.19 to 0.10 μg/kg, i.e. dependent on actual AMH and body weight.

The daily FE 999049 dose will be fixed throughout the stimulationperiod. The minimum allowed daily FE 999049 dose is 6 μg. The maximumallowed daily FE 999049 dose is 12 μg. Dosing will continue until thecriterion for triggering of final follicular maturation has been met.Subjects can be treated with FE 999049 for a maximum of 20 days.Coasting is not allowed.

The complete FE 999049 dosing regimen is tabulated in detail in thefollowing Table:

AMH Daily dose Treatment concenteation fixed throught Minimum Maximumgroup (pmol/L) stimulation daily dose daily dose FE 999049  <15 12 μg —12 μg 15-16 0.19 μg/kg 6 μg 12 μg 17 0.18 μg/kg 6 μg 12 μg 18 0.17 μg/kg6 μg 12 μg 19-20 0.16 μg/kg 6 μg 12 μg 21-22 0.15 μg/kg 6 μg 12 μg 23-240.14 μg/kg 6 μg 12 μg 25-27 0.13 μg/kg 6 μg 12 μg 28-32 0.12 μg/kg 6 μg12 μg 33-39 0.11 μg/kg 6 μg 12 μg ≥40 0.10 μg/kg 6 μg 12 μg AMHconcentration will be rounded oft to integers. Subjects can be treatedfor a maximum of 20 days.

The FE 999049 preparation is administered as a single daily subcutaneousinjection in the abdomen. The dose must not be split into twoinjections. To minimise local injection site reactions, it is advisableto change injection site regularly.

The first FE 999049 injection will take place at the clinic and will beperformed either by the trial medication delegate or the subject undersupervision by the trial medication delegate. Subsequent injections canbe done at home or at the clinic. The trial medication delegate willgive the subject instructions for how to administer FE 999049.

Calculation of the FE 999049 Dose and Setting the Dose on the FE 999049Pre-Filled Pen

The subject's serum AMH concentration will be available from the bloodsample taken at screening and analysed by a central laboratory usingElecsys® AMH assay from Roche Diagnostics. The AMH concentration will beprovided from the central laboratory directly to the eCRF. The subject'sbody weight will be measured at randomisation using a calibrated scaleand performed without shoes and overcoat. The body weight result will beentered into the eCRF. The FE 999049 dosing algorithm has beenprogrammed in the eCRF, which calculates the FE 999049 dose based on thesubject's AMH and body weight.

The FE 999049 pre-filled injection pen is intended for subcutaneousadministration of FE 999049. It is a non-sterile needle-based disposabledevice with integrated non-replaceable 3 mL cartridge containing theliquid FE 999049 drug product. Each cartridge holds multiple doses, thesize of which are adjustable by the user. It is possible to set dosesfrom 0.33 μg to 20.0 μg in increments of 0.33 μg. The FE 999049pre-filled injection pen has a dosing scale numbered from 0 to 20 μg.Each number is separated by two lines, each line representing 0.33 μg.The pre-filled injection pen can be set to deliver doses rounded to thenearest 0.33 μg. Rounding off of the calculated dose may be needed, asin this example of a subject weighing 75.0 kg with an AMH level of 35pmol/L for whom the calculated dose is 8.25 μg (0.11 μg/kg*75.0 kg),which will then be rounded to 8.33 μg, i.e. 8 μg+1 line on the pen. TheeCRF will provide the calculated dose in an output that matches thenumbers and lines on the pre-filled injection pen; i.e. any rounding offwill be done automatically prior to providing the subject's calculateddose.

The trial medication delegate will be instructed and trained in thecorrect use of the pre-filled injection pen, so that correctinstructions can be provided to the subject.

5.1.2 FOLLISTIM Dosing Regimen

For subjects randomised to FOLLISTIM, the dosing regimen is withinlabelling. The starting dose of FOLLISTIM is 150 IU and fixed for thefirst five stimulation days, after which it may be adjusted by 75 IUbased on the individual response. The maximum daily FOLLISTIM doseallowed is 375 IU. Dosing will continue until the criterion fortriggering of final follicular maturation has been met. Subjects can betreated with FOLLISTIM for a maximum of 20 days. Coasting is notallowed. The FOLLISTIM dosing regimen is shown in detail in thefollowing Table.

Starting dose Daily dose Minimum Maximum Treatment stimulationstimulation day daily daily group day 1-5 6 and onwards dose doseFOLLISTIM 150 IU Adjustments of 75 IU 375 IU 75 IU allowed according tothe individual response. Subjects can be treated for a maximum of 20days.

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1. A composition for use in the treatment of infertility in a patient having AMH≥15 pmol/L and bodyweight <60 kg, the composition comprising a daily dose of, or a daily dose equivalent to, 6 to 8 μg recombinant FSH.
 2. A composition for use according to claim 1, wherein the treatment of infertility includes determining the serum AMH level and bodyweight of the patient.
 3. A composition for use in the treatment of infertility in a patient identified as having AMH 15 pmol/L and identified as having bodyweight <60 kg, the composition comprising a daily dose of, or a daily dose equivalent to, 6 to 8 μg recombinant FSH.
 4. A composition for use according to claim 3, wherein the treatment of infertility includes a step of identifying the patient based on the serum AMH level and bodyweight of the patient.
 5. A composition for use according to any preceding claim for treatment of a patient having, or identified as having, bodyweight <59 kg, for example <56 kg, for example <55 kg, for example <52 kg, for example <50 kg, for example <45 kg, for example <42 kg, for example <31.5 kg.
 6. A composition for use according to any preceding claim for treatment of a patient having, or identified as having, AMH≥16 pmol/L, for example AMH≥19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28 pmol/L, for example AMH≥30 pmol/L, for example AMH≥40 pmol/L.
 7. A composition for use according to any preceding claim for treatment of a patient identified as having bodyweight <52 kg and AMH≥26 pmol/L.
 8. A composition for use according to claim 7 wherein the treatment of infertility includes a step of identifying the patient based on the serum AMH level and bodyweight of the patient, and a step of administering the dose to the patient having AMH≥26 pmol/L and bodyweight <52 kg.
 9. A composition for use according to any preceding claim, for treatment of infertility in an Asian patient.
 10. A composition for use according to any preceding claim comprising a daily dose of 6 μg recombinant FSH.
 11. A composition for use according to any preceding claim wherein the FSH is recombinant FSH.
 12. A composition for use according to any preceding claim wherein the recombinant FSH includes α2,3- and α2,6-sialylation.
 13. A medicament for treatment of infertility in an Asian (e.g. Japanese) patient comprising recombinant follicle stimulating hormone (FSH); wherein the medicament is administered to an Asian (e.g. Japanese) patient identified as having serum AMH level of ≥15 pmol/L and bodyweight less than 60 kg; and wherein the medicament is administered at a daily dose of, or daily dose equivalent to, 6 to 8 μg recombinant FSH.
 14. A medicament for use according to claim 14, wherein the treatment of infertility includes a step of determining the serum AMH level and bodyweight of the patient, and a step of administering the dose to a patient having the defined serum AMH level and bodyweight.
 15. A method of treatment of infertility comprising a step of administering a daily dose of, or a daily dose equivalent to, 6 to 8 μg recombinant FSH to a patient (e.g. a female patient) identified as having AMH≥15 pmol/L (for example AMH≥16 pmol/L, for example AMH 19 pmol/L, for example AMH≥26 pmol/L, for example AMH≥28 pmol/L, for example AMH≥40 pmol/L) and identified as having bodyweight <60 kg (e.g. bodyweight <55 kg, for example <52 kg, for example <50 kg, for example <45 kg).
 16. A composition for use in the treatment of infertility in a patient having AMH≥26 pmol/L and bodyweight <52 kg, the composition comprising a daily dose of 6 to 8 μg recombinant FSH.
 17. A composition for use in the treatment of infertility in a patient having AMH≥26 pmol/L and bodyweight <61 kg, the composition comprising a daily dose of, or a daily dose equivalent to, 6 to 8 μg recombinant FSH. 